The clinical objective in treatment of peptic ulcer disease is to decrease gastric acid secretion, based on the principle "no acid, no ulcer." Traditional peptic ulcer disease therapy involves control of diet and the use of antacids and anticholinergics.
There is evidence indicating that histamine may be the final common pathway for stimulation of gastric secretion. This effect of histamine is mediated via H.sub.2 receptors and is not inhibited by the classical antihistamines, which are H.sub.1 receptor blockers. A number of specific H.sub.2 receptor blocking agents (H.sub.2 receptor antagonists) are now known. These compounds inhibit basal acid secretion, as well as secretion by other known gastric acid stimulants, and are useful in the treatment of peptic ulcers.
Burimamide (IIa) was the first clinically effective H.sub.2 receptor antagonist. It inhibits gastric secretion in animals and man, but oral absorption is poor.
______________________________________ ##STR5## II IIa; R.sup.2H, ZCH.sub.2, XSBurimamide b; R.sup.2CH.sub.3, ZS, XSMetiamide c; R.sup.2CH.sub.3, ZS, XNCNCimetidine ______________________________________
Metiamide (IIb), a subsequently evaluated H.sub.2 antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (IIc) is as effective an H.sub.2 antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug. The half-life of cimetidine is relatively short, thereby necessitating a therapeutic regimen of multi daily doses of 200 mg. tablets. There is thus a need for anti-ulcer agents which are longer acting and/or more potent than cimetidine.
Reviews on the development of H.sub.2 antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13 (1976), and in references cited therein. Relevant patents are as follows:
1. U.S. Pat. No. 3,950,333 discloses inhibitors of histamine-stimulated gastric secretion having the formula ##STR6## wherein A, taken together with the carbon atom, represents an unsaturated heterocyclic ring containing at least one nitrogen and may contain an additional hetero atom such as sulfur or oxygen, X.sub.1 is inter alia (lower)alkyl, X.sub.2 is inter alia hydrogen, k is 0 to 2, m is 2, or 3, provided that the sum of k and m is 3 or 4, Y is oxygen, sulfur or NH, E is NR.sub.2 in which R.sub.2 is hydrogen, nitro or cyano, and R.sub.1 is hydrogen, (lower)alkyl or di(lower)alkylamino-(lower)alkyl.
2. Belgian Pat. No. 804,144 (Farmdoc 19437V) discloses inhibitors of histamine-stimulated gastric acid secretion having the formula ##STR7## in which HET is a 5 or 6 membered heterocyclic ring containing nitrogen, which may be substituted inter alia by alkyl, m and n are 0-4 and the sum of m and n is from 2 to 4, Z is sulfur, oxygen, NH or CH.sub.2, and R.sub.1 is hydrogen or (lower)alkyl.
3. Belgian Pat. No. 841,814 (Farmdoc 90568X) discloses inhibitors of histamine-stimulated gastric secretion having the formula ##STR8## in which HET is one of eight named heterocyclic rings (including imidazole) which may be substituted inter alia by (lower)alkyl, Z is sulfur or CH.sub.2, X is S, CHNO.sub.2, NCN or NH, Y is NH.sub.2, (lower)alkylamino, di(lower)alkylamino, (lower)alkoxy, phenylethyl, imidazolylethyl, allyl, trifluoroethyl or (CH.sub.2).sub.n R in which n is 1-12 and R is OH, (lower)alkoxy, NH.sub.2 or (lower)alkylamino; provided that, when X is NH, Y is trifluoroethyl or (CH.sub.2).sub.n R; and when X is NCN, Y may not be amino or (lower)alkyl.
This patent exemplifies and specifically claims the alkenyl compound of the formula ##STR9##
4. U.S. Pat. No. 3,894,151 discloses methods of inhibiting H.sub.1 and H.sub.2 histamine receptors, and compositions containing an antihistamine plus an H.sub.2 histamine receptor inhibitor, wherein the H.sub.2 histamine inhibitor is selected from the following groups:
(a) Thioureas of the formula ##STR10## wherein A, taken together with the carbon and nitrogen, is an unsaturated heterocyclic ring, X is inter alia (lower)alkyl, n is 3-6, and R is hydrogen, (lower)alkyl, benzoyl or optionally substituted phenylethyl.
(b) Compounds of the formula ##STR11## wherein A, taken together with the carbon, is an unsaturated heterocyclic ring containing at least one nitrogen, X.sub.1 is inter alia (lower)alkyl, X.sub.2 is inter alia hydrogen, k is 0 to 2 and m is 2-3, provided that the sum of k and m is 3 or 4, Y is oxygen, sulfur or NH, E is oxygen, sulfur or NR.sub.2 in which R.sub.2 is hydrogen, nitro or cyano, and R.sub.1 is hydrogen, (lower)alkyl, benzoyl or di(lower)alkylamino-(lower)alkyl.
(c) Amidine derivatives of the formula ##STR12## wherein A, taken together with the carbon and nitrogen, is an unsaturated 5-6 membered heterocyclic ring, X is inter alia (lower)alkyl, n is 2-5, R.sub.1 is inter alia (lower)alkyl; --NHR.sub.3 or --SR.sub.4, R.sub.2 is inter alia alkyl containing from 1-4 carbons or, when R.sub.1 is --NHR.sub.3, cyano or nitro, R.sub.3 is inter alia hydrogen, methyl or amino, R.sub.4 is inter alia alkyl containing 1-6 carbons or alkenyl or alkynyl containing 2-6 carbons.
(d) Isothioureas having the formula ##STR13## wherein A, taken together with the carbon and nitrogen, is an unsaturated 5 or 6 membered heterocyclic ring, X is hydrogen, halogen or benzyl, n is 2-4, R.sub.1 is hydrogen or (lower)alkyl, R.sub.2 is hydrogen, (lower)alkyl, amino or benzyl, or R.sub.1 and R.sub.2 taken together form an ethylene bridge.
(e) Amidines of the formula ##STR14## wherein n is 3 or 4.
The disclosures of U.S. Pat. Nos. 3,954,982 (a divisional of the above) and 4,000,302 (a continuation-in-part of the above) are substantially the same as that of U.S. Pat. No. 3,894,151.
5. Belgian Pat. No. 843,840 (Farmdoc 05613Y) discloses histamine H.sub.2 receptor antagonists having the formula ##STR15## wherein n is 2-3, Z is sulfur or CH.sub.2, Y is inter alia lower alkyl, and X is inter alia NCN.
Numerous other inhibitors of gastric acid secretion are known, but are considered much less relevant than those cited above because of still greater differences in structure from the instantly claimed compounds. The following patent covers compounds which are grossly different in structure from those claimed herein, but is cited as an example of compounds including alkynyl groups.
6. U.S. Pat. No. 3,897,555 discloses compounds of the formula ##STR16## wherein R.sub.1 is one of 8 named heterocyclic rings (not including imidazole), R.sub.2 is inter alia hydrogen, (lower)alkyl, (lower)alkenyl or allyloxy, R.sub.3 is an allyl or propargyl group which may be substituted by methyl or ethyl groups, said R.sub.3 having 3-6 carbon atoms.